Project Summary Pain is the most common reason that patients seek medical attention. Acute pain is an essential indicator of current or impending tissue damage. However, chronic pain is a maladaptive state with strong affective, biological, and psychological components. Chronic pain is extremely costly and has strong negative effects on sufferers? quality of life. Existing treatments for chronic pain, including opioid analgesics, are relatively ineffective. Perhaps as a result of the lack of efficacious treatments, it has been recently reported that nearly 25% of individuals suffering from chronic oral and/or musculoskeletal pain self-medicate through the oral consumption of alcohol. Indeed, alcohol interacts with a wide range of relevant pharmacologic targets capable of modulating the experience of pain. However, the biological mechanisms underlying this intuitive interaction are not well established. This relationship is important to understand because alcohol analgesia may act as a potent negative reinforcer for alcohol intake, which, in turn, can have adverse health effects by increasing risk of developing an alcohol use disorder. Familial risk for alcoholism, along with sex and certain mood/personality factors, may act as critical modulators of individual sensitivity to alcohol analgesia. However, it is currently unclear whether this sensitivity is the result of neurobiological, and/or learned factors. By characterizing independent contributions of each of these factors, this proposal will improve understanding of the interplay between pain/alcohol sensitivity, sex, and family history of alcoholism as a modulator of sensitivity to alcohol analgesia. These efforts will inform further research and clinical/translational efforts regarding risk associated with self-medication of pain by consuming alcohol. Critically, the impact of these factors on the functional neural correlates of alcohol analgesia will also be determined, improving mechanistic understanding of alcohol analgesia.